PROJECT SUMMARY This proposal aims to develop a new, small molecule drug to be advanced into human clinical trials for the treatment of cocaine addiction. According to the National Institute on Drug Abuse, illicit drug use cost the United States more than $700 billion annually in expenses related to crime, lost work productivity and health care. Approximately 1.5 million Americans aged 12 or older have used cocaine in the past month, and cocaine addiction is an unmet medical need for which there are no adequate FDA-approved therapeutics. Our team proposes to develop a CNS-penetrant inhibitor of the bromodomain and extraterminal domain (BET) family of proteins. This will be a first-in-class drug with a novel, innovative mechanism of action that has not been explored previously in human clinical trials to treat addiction. Our preliminary data demonstrate that BET proteins are upregulated and recruited to promoter regions of addiction-related genes in the nucleus accumbens following repeated cocaine administration and that inhibition of these proteins with a BET inhibitor attenuates transcriptional and behavioral responses to cocaine. Thus, BET inhibitors are potentially breakthrough drugs for treating cocaine seeking and taking behaviors. However, currently available BET inhibitors have several limitations (poor brain penetration, high microsomal clearance, etc.) and are unsuitable as drugs for CNS-related disease. This Phase I STTR seeks to address the liabilities of the currently available BET inhibitors, which have limited distribution to brain. Epigenetix Inc. has identified a new BET inhibitor (EP11313) with significantly improved brain distribution. Therefore, the goal of the project is to learn if EP11313 has benefit in the animal models of addiction with adequate safety and tolerability. This proposal has the following Specific Aims. Aim 1 will evaluate the efficacy of EP11313 in an animal model of addiction using intravenous cocaine self-administration (short and long-access) procedure. In Aim 2, EP11313 will be evaluated for off-target activity against a panel of GPCR, ion channels, transporters and the cardiac hERG channel. In Aim 3, in vivo CNS safety of EP11313 will be evaluated using a functional observational battery. The STTR project will transition to an SBIR for the preclinical development of EP11313. The Phase II SBIR will evaluate the efficacy of EP11313 in non-human primate models of addiction, assess pharmacokinetics in the selected non-rodent species for toxicology, provide IND enabling data and illicit venture capital investment for potential clinical trials.